Project 1 will oversee vaccine trials in rhesus macaques and develop DNA immunogens. Vaccine trials will use DNA, protein, and combinations of DNA and protein for immunizations. The purpose of the protein boost is to boost the titers of neutralizing antibody over those achievable with DNA alone. Two major vaccine trails will be undertaken. The first will use a DNA-expressed non-infectious SHIV 89.6 virus-like-particle (VLP) to prime macaques followed by protein boosts. This trial will define the utility of co-transfected GGM-CSF plus IL-12 or IL-18 for increasing protective efficacy, evaluated whether a random ubiquitinated library improves protective efficacy, and test whether intramuscular (i.m.) and gene gun (g.g) DNA immunizations differ in protective efficacy. While the first trial is in progress, novel concepts for improving and height and longevity of DNA-raised neutralizing antibody responses will be explored in rodent models. Specifically, we will test the ability of oligomeric gp- 140-universal-helper-epitope fusions to increase the height, longevity and avidity of neutralizing antibody responses. The second vaccine trial will build on positive results obtained in the first trial as well as test promising concepts identified during the first 3 years of the program in Projects 1 and 2. Project 1 will follow antibody responses in the vaccine trials for ELISA and neutralizing activity, and avidity maturation. Cell- mediated immune responses will be assessed in Projects 3 and 4.